Sphingosine kinase-1 inhibition sensitizes curcumin-induced growth inhibition and apoptosis in ovarian cancer cells

被引:53
作者
Yang, Yan-li [1 ]
Ji, Chao [2 ]
Cheng, Lei [1 ]
He, Li [3 ]
Lu, Chun-cheng [4 ]
Wang, Rong [5 ]
Bi, Zhi-gang [6 ]
机构
[1] Nanjing Med Univ, Dept Otorhinolaryngol, Affiliated Hosp 1, Nanjing, Jiangsu, Peoples R China
[2] Nanjing Med Univ, Dept Dermatol, Affiliated Hosp 1, Nanjing, Jiangsu, Peoples R China
[3] Kunming Med Univ, Dept Dermatol, Affiliated Hosp 1, Kunming, Peoples R China
[4] Nanjing Med Univ, Key Lab Reprod Med, Sch Publ Hlth, Nanjing, Jiangsu, Peoples R China
[5] Nanjing Med Univ, Lab Reprod Med, Res Ctr Bone & Stem Cells, Nanjing, Jiangsu, Peoples R China
[6] Nanjing Med Univ, Dept Dermatol, BenQ Med Ctr, Nanjing, Jiangsu, Peoples R China
关键词
CERAMIDE-INDUCED APOPTOSIS; PROTEIN PHOSPHATASE; CARCINOMA-CELLS; JNK ACTIVATION; P38; MAPK; PATHWAY; MELANOMA; AKT; OVEREXPRESSION; ACCUMULATION;
D O I
10.1111/j.1349-7006.2012.02335.x
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Recent published studies suggest that increasing levels of ceramides enhance the chemo-sensitivity of curcumin. Using in vitro approaches, we analyzed the impact of sphingosine kinase-1 (SphK-1) inhibition on ceramide production, and evaluated SphK1 inhibitor II (SKI-II) as a potential curcumin chemo-sensitizer in ovarian cancer cells. We found that SphK1 is overexpressed in ovarian cancer patients' tumor tissues and in cultured ovarian cancer cell lines. Inhibition of SphK1 by SKI-II or by RNA interference (RNAi) knockdown dramatically enhanced curcumin-induced apoptosis and growth inhibition in ovarian cancer cells. SKI-II facilitated curcumin-induced ceramide production, p38 activation and Akt inhibition. Inhibition of p38 by the pharmacological inhibitor (SB 203580), a dominant-negative expression vector, or by RNAi diminished curcumin and SKI-II co-administration-induced ovarian cancer cell apoptosis. In addition, restoring Akt activation introducing a constitutively active Akt, or inhibiting ceramide production by fumonisin B1 also inhibited the curcumin plus SKI-II co-administration-induced in vitro anti-ovarian cancer effect, suggesting that ceramide accumulation, p38 activation and Akt inhibition are downstream effectors. Our findings suggest that low, well-tolerated doses of SKI-II may offer significant improvement to the clinical curcumin treatment of ovarian cancer. (Cancer Sci 2012; 103: 15381545)
引用
收藏
页码:1538 / 1545
页数:8
相关论文
共 37 条
[1]   Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions [J].
Aarts, M ;
Liu, YT ;
Liu, LD ;
Besshoh, S ;
Arundine, M ;
Gurd, JW ;
Wang, YT ;
Salter, MW ;
Tymianski, M .
SCIENCE, 2002, 298 (5594) :846-850
[2]   Curcurnin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element [J].
Balogun, E ;
Hoque, M ;
Gong, PF ;
Killeen, E ;
Green, CJ ;
Foresti, R ;
Alam, J ;
Motterlini, R .
BIOCHEMICAL JOURNAL, 2003, 371 :887-895
[3]   Curcumin as an Anti-Cancer Agent: Review of the Gap Between Basic and Clinical Applications [J].
Bar-Sela, G. ;
Epelbaum, R. ;
Schaffer, M. .
CURRENT MEDICINAL CHEMISTRY, 2010, 17 (03) :190-197
[4]   Fas- or ceramide-induced apoptosis is mediated by a rad-regulated activation of jun N-terminal kinase p38 kinases and GADD153 [J].
Brenner, B ;
Koppenhoefer, U ;
Weinstock, C ;
Linderkamp, O ;
Lang, F ;
Gulbins, E .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (35) :22173-22181
[5]   Ceramide induces p38 MAPK and JNK activation through a mechanism involving a thioredoxin-interacting protein-mediated pathway [J].
Chen, Chia-Ling ;
Lin, Chiou-Feng ;
Chang, Wen-Tsan ;
Huang, Wei-Ching ;
Teng, Chiao-Fang ;
Lin, Yee-Shin .
BLOOD, 2008, 111 (08) :4365-4374
[6]  
DOBROWSKY RT, 1993, J BIOL CHEM, V268, P15523
[7]   Chemopreventive and therapeutic effects of curcumin [J].
Duvoix, A ;
Blasius, R ;
Delhalle, S ;
Schnekenburger, M ;
Morceau, F ;
Henry, E ;
Dicato, M ;
Diederich, M .
CANCER LETTERS, 2005, 223 (02) :181-190
[8]   Sphingosine kinase 1 is a relevant molecular target in gastric cancer [J].
Fuereder, Thorsten ;
Hoeflmayer, Doris ;
Jaeger-Lansky, Agnes ;
Rasin-Streden, Doris ;
Strommer, Sabine ;
Fisker, Niels ;
Hansen, Bo J. ;
Crevenna, Richard ;
Wacheck, Volker .
ANTI-CANCER DRUGS, 2011, 22 (03) :245-252
[9]   Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration [J].
Garcea, G ;
Jones, DJL ;
Singh, R ;
Dennison, AR ;
Farmer, PB ;
Sharma, RA ;
Steward, WP ;
Gescher, AJ ;
Berry, DP .
BRITISH JOURNAL OF CANCER, 2004, 90 (05) :1011-1015
[10]   Curcumin as "Curecumin":: From kitchen to clinic [J].
Goel, Ajay ;
Kunnumakkara, Ajaikumar B. ;
Aggarwal, Bharat B. .
BIOCHEMICAL PHARMACOLOGY, 2008, 75 (04) :787-809